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Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same

a technology of carboxyl group and aporphine, which is applied in the field of pharmaceutically acceptable salts of aporphine compounds and carboxyl group-containing agents and methods for preparing the same, can solve the problems of nitrate tolerance, hypertension, and artery gradually narrowing and can become clogged, and achieves dysregulation of physiological processes

Inactive Publication Date: 2009-12-24
STANDARD CHEM & PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0057]The object of the present invention is to provide a novel pharmaceutically acceptable compound, i.e. a salt of an aporphine derivative and a carboxyl group-containing agent, in which the aporphine derivative and the carboxyl group-containing agent have effects on oxidative stress.

Problems solved by technology

As plaque builds up in an artery, the artery gradually narrows and can become clogged.
Inactivation of NO by superoxide anion limits the bioavailability of NO and leads to nitrate tolerance, vasoconstriction, and hypertension as well as atherosclerosis.
However, when ROS production is enhanced, dysregulation of physiological processes occurs.
O2− and other radicals may react with NO causing endothelial dysfunction.
Coronary heart disease patients with low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride levels, or both are at an increased risk of cardiovascular events.
Atherosclerosis is a major cause of death in elderly individuals.
Without glutathione, your body immune system would be greatly compromised, and left with little defense against toxins and disease.
Thrombolysis after acute myocardial infarction may lead to a number of adverse effects (reperfusion injury) such as myocardial stunning, arrhythmias and even myocardial damage and extension of the infarct size.

Method used

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  • Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same
  • Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same
  • Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

Preparation of Compound 1

[0118]

[0119]Northaliporphine (380 mg, 1.16 mmol), methanol (MeOH, 10 mL) and 2-[(2-methoxy-phenox)methyl]oxirane (167 mg, 0.92 mmol) were added into a 50 mL round bottom flask and stirred at 70° C. for 16 hours. The mixture was evaporated to dryness. The residue was purified by chromatography (silica gel: 70-230 mesh 30 g, mobile phase: 2% MeOH / CH2Cl2, v / v) to obtain Compound 1, Rf 0.15 (2% MeOH / CH2Cl2, v / v); Physical data were as follows: mp: 63-68° C. (CH2Cl2); IR(KBr)vmax: 3500, 2931, 1605, 1506, 1464, 1253, 1112 cm−1; 1H NMR (CDCl3, 500 MHz):δ 8.00 (s, 1H), 6.98-6.88 (m, 4H), 6.75 and 6.73 (s, 1H), 6.53 (s, 1H), 6.12 (brs, 1H), 4.24-4.07 (m, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 3.39-2.53 (m, 9H); EIMS (70 eV): m / z (%) 507 [M]+, 339 (100).

preparation example 2

Preparation of Compound 2

[0120]

[0121]Northaliporphine (260 mg, 0.794 mmol), MeOH (10 mL) and 2-chloro-N-(2,6-dimethyl-phenyl)acetamide (187 mg, 0.946 mmol) were added into a 50 mL two-necked round bottom flask. Then triethylamine (Et3N, 0.5 mL, 3.55 mmol) was dropped into the mixture, and the reaction was allowed to proceed at 60° C. for two days. The mixture was evaporated to dryness. The residue was partitioned with water (50 mL) and dichloromethane (50 mL×3), and the organic layers were collected. The organic layer was dried with anhydrous MgSO4 and then filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography (silica gel: 70-230 mesh 30 g, mobile phase: 2% MeOH / CH2Cl2, v / v) to obtain Compound 2, Rf 0.58 (2% MeOH / CH2Cl2, v / v); Physical data were as follows: mp: 205-207° C. (CH2Cl2); IR(KBr)vmax: 3312, 2945, 1663,1 604, 1511, 1477, 1258, 1087 cm−1; 1H NMR(CDCl3, 500 MHz):δ 8.99 (s, 1H), 8.02 (s, 1H), 7.10 (s, 3H), 6.76 (s, 1H), 6.56 (s, 1H), 6.1...

preparation example 3

Preparation of Compound 3

[0122]

[0123]Norglaucine (300 mg, 0.88 mmol), MgSO4 (1 g), MeOH (7 mL), 2-thiophenecarboxaldehyde (0.14 mL, 1.5 mmol) and AcOH (0.5 mL, 8.88 mmol) were added into a 100 mL two-necked round bottom flask and stirred at room temperature. Sodium cyanoborohydride (NaBH3CN, 100 mg, 1.58 mmol) was added into the mixture after 1 hour, and the reaction was allowed to proceed at 70° C. for 4 hours. The mixture was evaporated to dryness. The residue was partitioned with water (50 mL) and dichloromethane (50 mL×2), and the organic layers were collected. The organic layer was dried with anhydrous MgSO4 and then filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography (silica gel: 230-400 mesh 30 g, mobile phase: EA / Hex=1 / 2, v / v) to obtain Compound 3, Rf 0.77 (EA / Hex=1 / 1, v / v); Physical data were as follows: mp: 143-148° C. (CH2Cl2); IR(KBr)vmax: 2958, 1578, 1514, 1466, 1110 cm−1; 1H NMR(CDCl3, 400 MHz):δ 8.05 (s, 1H), 7.22-7.20 (m, 1H),...

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Abstract

The present invention discloses novel pharmaceutically acceptable salts of aporphine compounds and carboxyl-group containing agents. Also, the present invention discloses methods for preparing the pharmaceutically acceptable salts. These pharmaceutically acceptable salts are suitable for use in treating and / or preventing hyperglycemic disease and / or several oxidative stress related diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 61 / 074,246, entitled “APORPHINE DERIVATIVES, APORPHINE DERIVATIVES SALTS AND THEIR PHARMACEUTICAL USES” filed Jun. 20, 2008 under 35 USC & 119(e)(1).BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to some novel salts of aporphine compounds and methods for preparing the same and, more particularly, to pharmaceutically acceptable salts of aporphine compounds and carboxyl-group containing agents and methods for preparing the same.[0004]2. Description of Related Art[0005]A multitude of studies in experimental animals, together with clinical data, provide evidence that increased production of ROS (reactive oxygen species) are involved in the development and progression of cardiovascular disease including atherogenesis. In particular, the paper demonstrates various steps where oxidative stress could be inv...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/473
CPCA61K31/40A61K31/473A61K31/4453A61K31/192A61K31/197A61K31/216A61K45/06A61K31/401A61K31/41A61K31/4184A61K2300/00A61P3/10A61P9/00A61P9/12A61P13/12A61P25/28A61P35/00
Inventor FAN, CHIN-TSAILAI, CHENG-SHUNLIN, MEI-JUNG
Owner STANDARD CHEM & PHARMA
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